Solid state forms of Belumosudil and Belumosudil salts

ABSTRACT

The present disclosure encompasses solid state forms of Belumosudil, in embodiments crystalline polymorphs of Belumosudil or salts thereof, processes for preparation thereof, and pharmaceutical compositions thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of, and claims priority to and thebenefit of, International Patent Application No. PCT/US2021/070924,filed Jul. 22, 2021, which, in turn, claims the benefit of and priorityto, U.S. Provisional Application No. 63/054,918, filed Jul. 22, 2020;U.S. Provisional Application No. 63/075,368, filed Sep. 8, 2020; U.S.Provisional Application No. 63/104,329 filed Oct. 22, 2020; and U.S.Provisional Application No. 63/137,212, filed Jan. 14, 2021, the entiredisclosures of each of which are incorporated by reference herein.

FIELD OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Belumosudil, inembodiments crystalline polymorphs of Belumosudil or salts thereof,processes for preparation thereof, and pharmaceutical compositionsthereof.

BACKGROUND OF THE DISCLOSURE

Belumosudil,2-(3-(4-((1H-Indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide,has the following chemical structure:

Belumosudil is a ROCK2 inhibitor, and it is developed for the treatmentof Graft-Versus-Host Disease including Chronic Graft-Versus-HostDisease, Systemic Sclerosis including Diffuse Cutaneous SystemicSclerosis, Fibrosis including Idiopathic Pulmonary Fibrosis, PlaquePsoriasis, and Systemic Scleroderma.

The compound is described in International Publication No. WO2006/105081. Crystalline forms of Belumosudil are disclosed inInternational Publication No. WO 2021/129589.

Polymorphism, the occurrence of different crystalline forms, is aproperty of some molecules and molecular complexes. A single moleculemay produce a rise to a variety of polymorphs having distinct crystalstructures and physical properties like melting point, thermal behaviors(e.g., measured by thermogravimetric analysis (“TGA”), or differentialscanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infraredabsorption fingerprint, and solid state (¹³C) NMR spectrum. One or moreof these techniques may be used to distinguish different polymorphicforms of a compound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, changingthe dissolution profile in a favorable direction, or improving stability(polymorph as well as chemical stability) and shelf-life. Thesevariations in the properties of different salts and solid state formsmay also offer improvements to the final dosage form, for instance, ifthey serve to improve bioavailability. Different salts and solid stateforms and solvates of an active pharmaceutical ingredient may alsoproduce a rise to a variety of polymorphs or crystalline forms, whichmay in turn provide additional opportunities to assess variations in theproperties and characteristics of a solid active pharmaceuticalingredient.

Discovering new solid state forms and solvates of a pharmaceuticalproduct may yield materials having desirable processing properties, suchas ease of handling, ease of processing, storage stability, and ease ofpurification or as desirable intermediate crystal forms that facilitateconversion to other polymorphic forms. New solid state forms of apharmaceutically useful compound can also provide an opportunity toimprove the performance characteristics of a pharmaceutical product. Itenlarges the repertoire of materials that a formulation scientist hasavailable for formulation optimization, for example by providing aproduct with different properties, including a different crystal habit,higher crystallinity, or polymorphic stability, which may offer betterprocessing or handling characteristics, improved dissolution profile, orimproved shelf-life (chemical/physical stability). For at least thesereasons, there is a need for additional solid state forms (includingsolvated forms) of Belumosudil, and Belumosudil salts.

SUMMARY OF THE DISCLOSURE

The present disclosure provides crystalline polymorphs of Belumosudiland salts thereof, including Belumosudil Mesylate, Belumosudil Tosylateand/or Belumosudil Besylate, processes for preparation thereof, andpharmaceutical compositions thereof. These crystalline polymorphs can beused to prepare other solid state forms of Belumosudil, Belumosudilsalts and their solid state forms.

The present disclosure also provides uses of the said solid state formsof API or salts thereof, including Belumosudil Mesylate, BelumosudilTosylate and/or Belumosudil Besylate, in the preparation of other solidstate forms of Belumosudil or salts thereof.

The present disclosure provides crystalline polymorphs of Belumosudil orsalts thereof, including Belumosudil Mesylate, Belumosudil Tosylate andBelumosudil Besylate, for use in medicine, including for the treatmentof Graft-Versus-Host Disease including Chronic Graft-Versus-HostDisease, Systemic Sclerosis including Diffuse Cutaneous SystemicSclerosis, Fibrosis including Idiopathic Pulmonary Fibrosis, PlaquePsoriasis, Systemic Scleroderma. Particularly, the present disclosureprovides crystalline polymorphs of Belumosudil or salts thereof,including Belumosudil Mesylate, Belumosudil Tosylate and BelumosudilBesylate, for use in medicine, including for the treatment of ChronicGraft-Versus-Host Disease and/or Systemic Sclerosis.

The present disclosure also encompasses the use of crystallinepolymorphs of Belumosudil, or salts thereof, including BelumosudilMesylate, Belumosudil Tosylate and Belumosudil Besylate of the presentdisclosure for the preparation of pharmaceutical compositions and/orformulations.

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising crystalline polymorphs of Belumosudil or saltsthereof, including Belumosudil Mesylate, Belumosudil Tosylate andBelumosudil Besylate according to the present disclosure.

The present disclosure includes processes for preparing the abovementioned pharmaceutical compositions. The processes include combiningany one or a combination of the crystalline polymorphs of Belumosudil orsalts thereof, including Belumosudil Mesylate, Belumosudil Tosylate andBelumosudil Besylate with at least one pharmaceutically acceptableexcipient.

The crystalline polymorphs of Belumosudil or salts thereof, includingBelumosudil Mesylate, Belumosudil Tosylate and Belumosudil Besylate asdefined herein and the pharmaceutical compositions or formulations ofthe crystalline polymorph of Belumosudil or salts thereof, includingBelumosudil Mesylate, Belumosudil Tosylate and Belumosudil Besylate maybe used as medicaments, such as for the treatment of Graft-Versus-HostDisease including Chronic Graft-Versus-Host Disease, Systemic Sclerosisincluding Diffuse Cutaneous Systemic Sclerosis, Fibrosis includingIdiopathic Pulmonary Fibrosis, Plaque Psoriasis, Systemic Scleroderma.Particularly, the crystalline polymorphs of Belumosudil or saltsthereof, including Belumosudil Mesylate, Belumosudil Tosylate andBelumosudil Besylate as defined herein and the pharmaceuticalcompositions or formulations of the crystalline polymorph of Belumosudilor salts thereof, including Belumosudil Mesylate, Belumosudil Tosylateand/or Belumosudil Besylate may be used as medicaments, for thetreatment of Chronic Graft-Versus-Host Disease and/or SystemicSclerosis.

The present disclosure also provides methods of treatingGraft-Versus-Host Disease including Chronic Graft-Versus-Host Disease,Systemic Sclerosis including Diffuse Cutaneous Systemic Sclerosis,Fibrosis including Idiopathic Pulmonary Fibrosis, Plaque Psoriasis,Systemic Scleroderma, by administering a therapeutically effectiveamount of any one or a combination of the crystalline polymorphs ofBelumosudil or salts thereof, including Belumosudil Mesylate,Belumosudil Tosylate and Belumosudil Besylate of the present disclosure,or at least one of the above pharmaceutical compositions, to a subjectsuffering from Graft-Versus-Host Disease including ChronicGraft-Versus-Host Disease, Systemic Sclerosis including DiffuseCutaneous Systemic Sclerosis, Fibrosis including Idiopathic PulmonaryFibrosis, Plaque Psoriasis, Systemic Scleroderma, or otherwise in needof the treatment. Particularly, the present disclosure provides methodsof treating Chronic Graft-Versus-Host Disease and/or Systemic Sclerosis,by administering a therapeutically effective amount of any one or acombination of the crystalline polymorphs of Belumosudil or saltsthereof, including Belumosudil Mesylate, Belumosudil Tosylate andBelumosudil Besylate of the present disclosure, or at least one of theabove pharmaceutical compositions, to a subject suffering from ChronicGraft-Versus-Host Disease and/or Systemic Sclerosis, or otherwise inneed of the treatment.

The present disclosure also provides uses of crystalline polymorphs ofBelumosudil or salts thereof, including Belumosudil Mesylate,Belumosudil Tosylate and/or Belumosudil Besylate of the presentdisclosure, or at least one of the above pharmaceutical compositions,for the manufacture of medicaments for treating e.g., Graft-Versus-HostDisease including Chronic Graft-Versus-Host Disease, Systemic Sclerosisincluding Diffuse Cutaneous Systemic Sclerosis, Fibrosis includingIdiopathic Pulmonary Fibrosis, Plaque Psoriasis, Systemic Scleroderma,and particularly for treating Chronic Graft-Versus-Host Disease and/orSystemic Sclerosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an X-ray powder diffraction pattern (XRPD) of amorphousBelumosudil.

FIG. 2 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil Form B1.

FIG. 3 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil Form B2.

FIG. 4 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil Form B3.

FIG. 5 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil Mesylate Form M1.

FIG. 6 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil form B4.

FIG. 7 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil Mesylate form M2.

FIG. 8 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil Mesylate form M3.

FIG. 9 shows a characteristic X-ray powder diffraction pattern (XRPD) ofBelumosudil form B5.

FIG. 10 shows a characteristic X-ray powder diffraction pattern (XRPD)of amorphous Belumosudil Mesylate.

FIG. 11 shows a characteristic X-ray powder diffraction pattern (XRPD)of Belumosudil Mesylate form M4.

FIG. 12 shows a characteristic X-ray powder diffraction pattern (XRPD)of Belumosudil Mesylate form M5.

FIG. 13 shows a characteristic X-ray powder diffraction pattern (XRPD)of Belumosudil Besylate form BS1.

FIG. 14 shows a characteristic X-ray powder diffraction pattern (XRPD)of Belumosudil Tosylate form T1.

FIG. 15 shows a characteristic X-ray powder diffraction pattern (XRPD)of Belumosudil Tosylate form T2.

FIG. 16 shows a characteristic solid state ¹³C NMR spectrum of Form M1of Belumosudil Mesylate (full range 200-0 ppm).

FIG. 17 shows a characteristic solid state ¹³C NMR spectrum of Form M1of Belumosudil Mesylate 200-100 ppm).

FIG. 18 shows a characteristic solid state ¹³C NMR spectrum of Form M1of Belumosudil Mesylate (100-0 ppm).

FIG. 19 shows a characteristic solid state ¹³C NMR spectrum of Form M2of Belumosudil Mesylate (full range 200-0 ppm).

FIG. 20 shows a characteristic solid state ¹³C NMR spectrum of Form M2of Belumosudil Mesylate 200-100 ppm).

FIG. 21 shows a characteristic solid state ¹³C NMR spectrum of Form M2of Belumosudil Mesylate (100-0 ppm).

FIG. 22 shows a characteristic solid state ¹³C NMR spectrum of Form BS1of Belumosudil Besylate (full range 200-0 ppm).

FIG. 23 shows a characteristic solid state ¹³C NMR spectrum of Form BS1of Belumosudil Besylate 200-100 ppm).

FIG. 24 shows a characteristic solid state ¹³C NMR spectrum of Form BS1of Belumosudil Besylate (100-0 ppm).

FIG. 25 shows a scanning electron microscopy (SEM) image of particles ofForm BS1 of Belumosudil Besylate.

FIG. 26 shows a characteristic solid state ¹³C NMR spectrum of Form T1of Belumosudil Tosylate (full range 200-0 ppm).

FIG. 27 shows a characteristic solid state ¹³C NMR spectrum of Form T1of Belumosudil Tosylate 200-100 ppm).

FIG. 28 shows a characteristic solid state ¹³C NMR spectrum of Form T1of Belumosudil Tosylate (100-0 ppm).

FIG. 29 shows a scanning electron microscopy (SEM) image of particles ofForm T1 of Belumosudil Tosylate.

FIG. 30 shows a characteristic solid state ¹³C NMR spectrum of Form T2of Belumosudil Tosylate (full range 200-0 ppm).

FIG. 31 shows a characteristic solid state ¹³C NMR spectrum of Form T2of Belumosudil Tosylate 200-100 ppm).

FIG. 32 shows a characteristic solid state ¹³C NMR spectrum of Form T2of Belumosudil Tosylate (100-0 ppm).

FIG. 33 shows a scanning electron microscopy (SEM) image of particles ofForm T2 of Belumosudil Tosylate.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Belumosudil andsalts thereof, including crystalline polymorphs of Belumosudil and saltsthereof, including Belumosudil Mesylate, Belumosudil Tosylate and/orBelumosudil Besylate processes for preparation thereof, andpharmaceutical compositions thereof.

Solid state properties of Belumosudil, Belumosudil salts, andcrystalline polymorphs thereof can be influenced by controlling theconditions under which Belumosudil and Belumosudil salts, andcrystalline polymorphs thereof are obtained in solid form.

A solid state form (or polymorph) may be referred to herein aspolymorphically pure or as substantially free of any other solid state(or polymorphic) forms. As used herein in this context, the expression“substantially free of any other forms” will be understood to mean thatthe solid state form contains about 20% (w/w) or less, about 10% (w/w)or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w)or less, or about 0% of any other forms of the subject compound asmeasured, for example, by XRPD. Thus, a crystalline polymorph ofBelumosudil or Belumosudil salt, described herein as substantially freeof any other solid state forms would be understood to contain greaterthan about 80% (w/w), greater than about 90% (w/w), greater than about95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w),or about 100% of the subject crystalline polymorph of Belumosudil orBelumosudil salt. In some embodiments of the disclosure, the describedcrystalline polymorph of Belumosudil or Belumosudil salt, may containfrom about 1% to about 20% (w/w), from about 5% to about 20% (w/w), orfrom about 5% to about 10% (w/w) of one or more other crystallinepolymorph of the same Belumosudil or Belumosudil salt. Similarly, acrystalline polymorph of Belumosudil salt (e.g. Belumosudil Mesylate,Belumosudil Tosylate or Belumosudil Besylate) described herein assubstantially free of any other solid state forms would be understood tocontain greater than about 80% (w/w), greater than about 90% (w/w),greater than about 95% (w/w), greater than about 98% (w/w), greater thanabout 99% (w/w), or about 100% of the subject crystalline polymorph ofthe Belumosudil salt (e.g. Belumosudil Mesylate, Belumosudil Tosylate orBelumosudil Besylate). In some embodiments of the disclosure, thedescribed crystalline polymorph of Belumosudil salt (e.g., BelumosudilMesylate, Belumosudil Tosylate or Belumosudil Besylate) may contain fromabout 1% to about 20% (w/w), from about 5% to about 20% (w/w), or fromabout 5% to about 10% (w/w) of one or more other crystalline polymorphof the same Belumosudil salt (e.g., Belumosudil Mesylate, BelumosudilTosylate or Belumosudil Besylate).

Depending on which other crystalline polymorphs a comparison is made,the crystalline polymorphs of Belumosudil and Belumosudil salts (e.g.Belumosudil Mesylate, Belumosudil Tosylate or Belumosudil Besylate) ofthe present disclosure may have advantageous properties selected from atleast one of the following: chemical purity, flowability, solubility,dissolution rate, morphology or crystal habit, stability, such aschemical stability as well as thermal and mechanical stability withrespect to polymorphic conversion, stability towards dehydration and/orstorage stability, low content of residual solvent, a lower degree ofhygroscopicity, flowability, and advantageous processing and handlingcharacteristics such as compressibility and bulk density.

A solid state form, such as a crystal form or an amorphous form, may bereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which cannot necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to certain factors suchas, but not limited to, variations in instrument response and variationsin sample concentration and purity, which are well known to the skilledperson. Nonetheless, the skilled person would readily be capable ofcomparing the graphical data in the Figures herein with graphical datagenerated for an unknown crystal form and confirm whether the two setsof graphical data are characterizing the same crystal form or twodifferent crystal forms. A crystal form of Belumosudil or Belumosudilsalt, referred to herein as being characterized by graphical data “asdepicted in” or “as substantially depicted in” a Figure will thus beunderstood to include any crystal forms of Belumosudil or Belumosudilsalt, characterized with the graphical data having such smallvariations, as are well known to the skilled person, in comparison withthe Figure.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline forms of Belumosudil, Belumosudil Mesylate,Belumosudil Tosylate and/or Belumosudil Besylate, relates to acrystalline form of Belumosudil or Belumosudil salt which does notinclude any crystalline water (or other solvents) in a defined,stoichiometric amount within the crystal. Moreover, an “anhydrous” formwould generally not contain more than 1% (w/w), of either water ororganic solvents as measured for example by TGA.

The term “solvate,” as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount.

As used herein, the term “isolated” in reference to crystallinepolymorph of Belumosudil, or Belumosudil salt (e.g., BelumosudilMesylate, Belumosudil Tosylate and/or Belumosudil Besylate) of thepresent disclosure corresponds to a crystalline polymorph of Belumosudilor Belumosudil salt, that is physically separated from the reactionmixture in which it is formed.

As used herein, unless stated otherwise, the XRPD measurements are takenusing copper Kα radiation wavelength 1.5418 Å. XRPD peaks reportedherein are measured using CuKα radiation, λ=1.5418 Å, typically at atemperature of 25±3° C.

As used herein, ¹³C NMR spectra are preferably measured at 125 MHz atmagic angle spinning (MAS) frequency ωr/2π=11 kHz

As used herein, unless stated otherwise, TGA analysis is preferablycarried out at a heating rate of 10° C./min to 250° C., preferably witha nitrogen flow of 40 ml/min.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature” or “ambient temperature”,often abbreviated as “RT.” This means that the temperature of the thingis close to, or the same as, that of the space, e.g., the room or fumehood, in which the thing is located. Typically, room temperature is fromabout 20° C. to about 30° C., or about 22° C. to about 27° C., or about25° C.

The amount of solvent employed in a chemical process, e.g., a reactionor crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending a5 grams of a material in 10 volumes of a solvent means that the solventis used in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding solvent X (1.5 v/v)to a 100 ml reaction mixture would indicate that 150 mL of solvent X wasadded.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, in some cases about 16 hours.

As used herein, the term “reduced pressure” refers to a pressure that isless than atmospheric pressure. For example, reduced pressure is about10 mbar to about 50 mbar.

As used herein and unless indicated otherwise, the term “ambientconditions” refer to atmospheric pressure and a temperature of 22-24° C.

The present disclosure includes a crystalline polymorph of Belumosudil,designated form B1. The crystalline Form B1 of Belumosudil may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 2 ;an X-ray powder diffraction pattern having peaks at 3.5, 6.9, 10.5, 24.9and 25.7 degrees 2-theta±0.2 degrees 2-theta; and combinations of thesedata.

Crystalline Form B1 of Belumosudil may be further characterized by anX-ray powder diffraction pattern having peaks at 3.5, 6.9, 10.5, 24.9and 25.7 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 9.4, 12.5, 15.7,18.9 and 19.7 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form B1 of Belumosudil may be alternatively characterized byan X-ray powder diffraction pattern having peaks at 3.5, 6.9, 9.4, 10.5,12.5, 15.7, 18.9, 19.7, 24.9, and 25.7 degrees 2-theta±0.2 degrees2-theta.

In one embodiment of the present disclosure, crystalline Form B1 ofBelumosudil is isolated.

Crystalline Form B1 of Belumosudil may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g., anXRPD pattern having peaks at 3.5, 6.9, 10.5, 24.9 and 25.7 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 2 , andcombinations thereof.

The present disclosure includes a crystalline polymorph of Belumosudil,designated form B2. The crystalline Form B2 of Belumosudil may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 3 ;an X-ray powder diffraction pattern having peaks at 3.8, 5.7, 7.6, 9.6and 25.9 degrees 2-theta±0.2 degrees 2-theta; and combinations of thesedata.

Crystalline Form B2 of Belumosudil may be further characterized by anX-ray powder diffraction pattern having peaks at 3.8, 5.7, 7.6, 9.6 and25.9 degrees 2-theta±0.2 degrees 2-theta, and also having any one, two,three, four or five additional peaks selected from 10.7, 15.4, 16.6,17.8 and 19.3 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form B2 of Belumosudil may be alternatively characterized byan X-ray powder diffraction pattern having peaks at 3.8, 5.7, 7.6, 9.6,10.7, 15.4, 16.6, 17.8, 19.3 and 25.9 degrees 2-theta±0.2 degrees2-theta.

In one embodiment of the present disclosure, crystalline Form B2 ofBelumosudil is isolated.

Crystalline Form B2 of Belumosudil may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g., anXRPD pattern having peaks at 3.8, 5.7, 7.6, 9.6 and 25.9 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 3 , andcombinations thereof.

The present disclosure includes a crystalline polymorph of Belumosudil,designated form B3. The crystalline Form B3 of Belumosudil may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 4 ;an X-ray powder diffraction pattern having peaks at 6.5, 8.4, 12.2, 19.6and 26.3 degrees 2-theta±0.2 degrees 2-theta; and combinations of thesedata.

Crystalline Form B3 of Belumosudil may be further characterized by anX-ray powder diffraction pattern having peaks at 6.5, 8.4, 12.2, 19.6and 26.3 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 14.7, 15.4,16.4, 18.8 and 22.5 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form B3 of Belumosudil may be alternatively characterized byan X-ray powder diffraction pattern having peaks at 6.5, 8.4, 12.2,14.7, 15.4, 16.4, 18.8, 19.6, 22.5, and 26.3 degrees 2-theta±0.2 degrees2-theta.

In one embodiment of the present disclosure, crystalline Form B3 ofBelumosudil is isolated.

Crystalline Form B3 of Belumosudil may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g., anXRPD pattern having peaks at 6.5, 8.4, 12.2, 19.6 and 26.3 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 4 , andcombinations thereof.

The present disclosure includes a crystalline polymorph of Belumosudil,designated form B4. The crystalline Form B4 of Belumosudil may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 6 ;an X-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 16.7and 17.2 degrees 2-theta±0.2 degrees 2-theta; and combinations of thesedata.

Crystalline Form B4 of Belumosudil may be further characterized by anX-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 16.7and 17.2 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 15.2, 18.7,24.1, 25.6 and 26.2 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form B4 of Belumosudil may be further characterized by anX-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9, 16.7and 17.2 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 15.2, 18.7,24.1, 25.6 and 26.2 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form B4 of Belumosudil may be alternatively characterized byan X-ray powder diffraction pattern having peaks at 8.3, 9.3, 11.9,15.2, 16.7, 17.2, 18.7, 24.1, 25.6, and 26.2 degrees 2-theta±0.2 degrees2-theta.

In one embodiment of the present disclosure, crystalline Form B4 ofBelumosudil is isolated.

Crystalline Form B4 of Belumosudil may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g., anXRPD pattern having peaks at 8.3, 9.3, 11.9, 16.7 and 17.2 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 6 , andcombinations thereof.

The present disclosure includes a crystalline polymorph of Belumosudil,designated form B5. The crystalline Form B5 of Belumosudil may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 9 ;an X-ray powder diffraction pattern having peaks at 6.1, 12.9, 16.2,16.8 and 19.2 degrees 2-theta±0.2 degrees 2-theta; and combinations ofthese data.

Crystalline Form B5 of Belumosudil may be further characterized by anX-ray powder diffraction pattern having peaks at 6.1, 12.9, 16.2, 16.8and 19.2 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 3.7, 9.4, 9.8,12.4 and 18.4 degrees 2-theta±0.2 degrees 2-theta.

Crystalline Form B5 of Belumosudil may be alternatively characterized byan X-ray powder diffraction pattern having peaks at 3.7, 6.1, 9.4, 9.8,12.4, 12.9, 16.2, 16.8, 18.4, and 19.2 degrees 2-theta±0.2 degrees2-theta.

In one embodiment of the present disclosure, crystalline Form B5 ofBelumosudil is isolated.

Crystalline Form B5 of Belumosudil may be characterized by each of theabove characteristics alone/or by all possible combinations, e.g., anXRPD pattern having peaks at 6.1, 12.9, 16.2, 16.8 and 19.2 degrees2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG. 9 , andcombinations thereof.

The present disclosure includes a crystalline polymorph of BelumosudilMesylate, designated form M1. The crystalline Form M1 of BelumosudilMesylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 5 ; an X-ray powder diffraction pattern having peaks at 7.1,17.2, 20.3, 21.5 and 25.5 degrees 2-theta±0.2 degrees 2-theta; a solidstate ¹³C NMR spectrum with characteristic peaks at 137.8, 133.8, 122.5,118.3 and 111.6 ppm±0.2 ppm; a solid state ¹³C NMR spectrum having thefollowing chemical shift absolute differences from reference peak at167.2 ppm±1 ppm: 29.4, 33.4, 44.7, 48.9 and 55.6 ppm±0.1 ppm; a solidstate ¹³C NMR spectrum substantially as depicted in any of FIGS. 16, 17and 18 ; and combinations of these data.

Crystalline Form M1 of Belumosudil Mesylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 7.1, 17.2, 20.3,21.5 and 25.5 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 8.4, 15.5,16.8, 19.5 and 22.1 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form M1 of Belumosudil Mesylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 7.1,8.4, 15.5, 16.8, 17.2, 19.5, 20.3, 21.5, 22.1 and 25.5 degrees2-theta±0.2 degrees 2-theta.

According to any aspect or embodiment as described herein, crystallineform M1 of Belumosudil Mesylate may be an anhydrous form, as can bedetermined by TGA. According to any aspect or embodiment as describedherein, crystalline form M1 of Belumosudil Mesylate may contain 0.5% w/wor less, or 0.2% w/w or less, or 0.1 wt % or less, of total residualsolvent. The residual solvent may be one or more polar solvents,preferably water, alcohols (particularly C₁₋₄ alcohols, especiallymethanol, ethanol, isopropanol, 1-propanol, or n-butanol) or halogenatedsolvents (particularly 2,2,2-trifluoroethanol or dichloromethane), orDMSO, or mixtures thereof. Particularly, crystalline form M1 ofBelumosudil Mesylate according to any aspect or embodiment of thedisclosure may contain 0.5% w/w or less, or 0.2% w/w or less, or 0.1 wt% or less, of total residual solvent, wherein the residual solvent is:ethanol, water, or DMSO, or a combination of ethanol, water and DMSO andwater, or a combination of ethanol and DMSO. Alternatively, crystallineform M1 of Belumosudil Mesylate according to any aspect or embodiment ofthe disclosure may contain 0.5% w/w or less, or 0.2% w/w or less, or 0.1wt % or less, of ethanol, or 0.5% w/w or less, or 0.2 w/w or less, or0.1 wt % or less, of a mixture of ethanol and DMSO.

In one embodiment of the present disclosure, crystalline Form M1 ofBelumosudil Mesylate is isolated. Particularly, crystalline form M1 ofBelumosudil Mesylate according to any aspect or embodiment of thedisclosure may be isolated.

According to any aspect or embodiment of the present disclosure,crystalline Form M1 of Belumosudil Mesylate is non-hygroscopic.Particularly, Form M1 of Belumosudil Mesylate according to any aspect orembodiment is polymorphically stable at up to 100% relative humidity atroom temperature for at least 7 days.

Crystalline Form M1 of Belumosudil Mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 7.1, 17.2, 20.3, 21.5 and 25.5degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.5 , and combinations thereof.

Crystalline form M1 of Belumosudil Mesylate may be prepared bycrystallisation from a mixture comprising Belumosudil Mesylate and oneor more polar solvents, preferably a polar organic solvent, andparticularly wherein the polar solvent is an alcohol or halogenatedsolvent, or mixtures thereof. Examples of suitable solvents include, butare not limited to, methanol, ethanol, isopropanol, 1-propanol,n-butanol, dichloromethane, and combinations thereof; and preferablyethanol, isopropanol, n-butanol or 1-propanol. In any aspect orembodiment of the present disclosure for preparing form M1, the processmay comprise:

-   -   (a) providing a mixture of Belumosudil Mesylate in at least one        polar solvent, optionally with heating;    -   (b) optionally stirring the mixture, optionally at elevated        temperature;    -   (c) optionally cooling the mixture, preferably to room        temperature;    -   (d) optionally stirring the cooled mixture; and    -   (e) optionally isolating crystalline form M1 of Belumosudil        Mesylate from the mixture.

The mixture in step (a) may be prepared by:

(i) providing a mixture of Belumosudil free base in a polar solvent;

(ii) combining the mixture with Methanesulfonic acid;

(iii) optionally heating the mixture; and

(iv) optionally adding a further polar solvent.

Preferably, the process for preparing Form M1 of Belumosudil Mesylateaccording to any embodiment described herein is carried out in theabsence of water or substantially in the absence of water, particularly2 wt % or less, 1 wt % or less, 0.5 wt % or less, 0.2 wt % or less, or0.1 wt % or less of water.

According to any embodiment of the process for preparing form M1, thesolvent in step (i) is preferably an organic solvent, particularlycomprising an alcohol, a halogenated solvent, or mixtures thereof.Preferably the solvent is selected from the group consisting ofmethanol, ethanol, isopropanol, 1-propanol, n-butanol, anddichloromethane or mixtures thereof, and particularly, ethanol,isopropanol, 1-propanol, n-butanol.

In step (i), the ratio of solvent to Belumosudil may be: about 10 toabout 40 ml per gram of Belumosudil, about 14 to about 35 ml per gram ofBelumosudil or about 16 to about 20 to about 32 ml per gram ofBelumosudil, or about 18 to about 24 ml per gram of Belumosudil, andoptionally about 20 ml per gram of Belumosudil. The mixture in step (i)may be a solution or a slurry.

In step (ii) of the process for preparing form M1, combining ofmethanesulfonic acid to Belumosudil may be in any order. Preferably,methanesulfonic acid may be added to the mixture of Belumosudil in thesolvent. The addition may be carried out portion-wise or dropwise. Themethanesulfonic acid is optionally added in an amount of: about 0.7 toabout 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents,about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalentsrelative to Belumosudil. Preferably, step (ii) comprises addingMethanesulfonic acid to the mixture of Belumosudil and solvent.

In step (iii) of the process for preparing form M1, the mixture may beoptionally heated. The heating may be to a temperature of about 30° C.to about 70° C., about 40° C. to about 60° C., about 45° C. to about 55°C., or about 50° C.

In step (iv), a further polar solvent may be added to the reactionmixture. The further solvent may be any solvent which is a poor solventfor Belumosudil Mesylate, i.e., a solvent in which Belumosudil Mesylatehas low solubility. The further polar solvent may be the same solvent asthat used in step (i)) or may be different. The further solvent ispreferably selected from the group consisting of methanol, ethanol,isopropanol, 1-propanol, n-butanol, and dichloromethane or mixturesthereof. Preferably, the further polar solvent in step (iv) is selectedfrom methanol, ethanol, isopropanol, 1-propanol, and n-butanol. Morepreferably, the further polar solvent in step (iv) is ethanol. Thefurther polar solvent in step (iv) can be added in any suitable amount.Preferably, the v/v ratio of the further polar solvent to the solvent instep (i) may be from: about 5:1 to about 1:5, or about 2:1 to about 1:2,or about 1.5:1 to about 1:1.5, or about 1.3:1 to about 1:1.3, andpreferably about 1:1.3.

Alternatively, according to any embodiment of the process for preparingForm M1, the mixture in step (a) may be prepared by:

-   -   (i-a) combining Belumosudil Mesylate with a polar solvent,        optionally with heating, to form a solution; and optionally    -   (ii-a) adding an organic antisolvent.

The polar solvent in step (i-a) is preferably an organic solvent, morepreferably selected from the group consisting of, 2,2,2-Trifluoroethanol(TFE), and DMSO or mixtures thereof. Particularly, the solvent isselected from the group consisting of TFE and DMSO. In step (i-a), theratio of solvent to Belumosudil Mesylate may be from: about 5 to about50 ml, about 7 to about 40 ml, about 9 to about 35 ml, or about 10V toabout 30 ml per gram of Belumosudil Mesylate.

The organic antisolvent in step (ii-a) can be any organic solvent inwhich Belumosudil Mesylate is poorly soluble. Preferably the organicantisolvent in step (ii-a) is selected from the group consisting ofacetonitrile, dioxane, methyl ethyl ketone, methyl t-butyl ketone,ethanol, isopropanol, 1-propanol, n-butanol, and more particularly,ethanol.

In any embodiment of the process for preparing form M1, the mixture instep (a) may be a solution or a slurry. The mixture in step (a) ispreferably in the form of a slurry. The mixture in step (a) may be atroom temperature, or may be heated. The heating may be to a temperatureof about 30° C. to about 70° C., about 40° C. to about 60° C., about 45°C. to about 55° C., or about 50° C. Alternatively, the mixture may be atroom temperature.

In any embodiment of the process for preparing Form M1, step (b) iscarried out, preferably by stirring at a temperature of: about 30° C. toabout 70° C., about 40° C. to about 60° C., about 45° C. to about 55°C., or about 50° C. Alternatively, step (b) may be carried out at roomtemperature. The stirring may be carried out for any suitable time.Typically, the stirring may be carried out over a period of about 10minutes to about 2 hours, about 20 minutes to about 1 hour, or about 45minutes.

In any embodiment of the process for preparing Form M1, step (c) iscarried out. Preferably, the cooling is to room temperature. Aftercooling, step (d) can be carried out, preferably by stirring the cooledmixture for a suitable time to prepare Belumosudil Mesylate Form M1. Thestirring may be carried out for any suitable time, preferably for about6 to about 96 hours, about 20 to about 80 hours, about 30 to about 50hours, or about 40 hours.

In any embodiment of the process, step (e) may be carried out by anysuitable method, for example by filtration, decantation or bycentrifuge. Preferably the isolation of the solid is by filtration or bycentrifuge, and more preferably by centrifuge.

In any embodiment the process may further comprise washing and/or dryingsteps.

The present disclosure includes a crystalline polymorph of BelumosudilMesylate, designated form M2. The crystalline Form M2 of BelumosudilMesylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 7 ; an X-ray powder diffraction pattern having peaks at 6.3,12.8, 15.8, 19.3 and 26.5 degrees 2-theta±0.2 degrees 2-theta; a solidstate ¹³C NMR spectrum with characteristic peaks at 156.1, 132.7, 135.5,119.8 and 110.9 ppm±0.2 ppm; a solid state ¹³C NMR spectrum having thefollowing chemical shift absolute differences from reference peak at166.9 ppm±1 ppm: 10.8, 34.2, 36.4, 47.1 and 56.0 ppm±0.1 ppm; a solidstate ¹³C NMR spectrum substantially as depicted in any of FIGS. 19, 20and 21 ; and combinations of these data.

Crystalline Form M2 of Belumosudil Mesylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 6.3, 12.8, 15.8,19.3 and 26.5 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 7.8, 20.4,23.7, 25.1 and 27.4 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form M2 of Belumosudil Mesylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 6.3,7.8, 12.8, 15.8, 19.3, 20.4, 23.7, 25.1, 26.5 and 27.4 degrees2-theta±0.2 degrees 2-theta.

According to any aspect or embodiment of the disclosure, crystallineform M2 of Belumosudil Mesylate may be a hydrate, preferably adi-hydrate. Alternatively, according to any aspect or embodiment of thepresent disclosure, crystalline form M2 of Belumosudil Mesylate maycontain about 1% to about 7% of water, preferably about 1.5 to about6.1% of water by weight.

In one embodiment of the present disclosure, crystalline Form M2 ofBelumosudil Mesylate is isolated. Particularly, crystalline form M2 ofBelumosudil Mesylate according to any aspect or embodiment of thedisclosure may be isolated.

According to any aspect or embodiment of the present disclosure,crystalline Form M2 of Belumosudil Mesylate is non-hygroscopic.Particularly, Form M2 of Belumosudil Mesylate according to any aspect orembodiment is polymorphically stable at up to 100% relative humidity atroom temperature for at least 7 days.

Crystalline Form M2 of Belumosudil Mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 6.3, 12.8, 15.8, 19.3 and 26.5degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.7 , and combinations thereof.

Crystalline form M2 of Belumosudil Mesylate may be prepared bycrystallisation from a mixture comprising Belumosudil Mesylate andwater, and optionally one or more polar organic solvents, preferablyalcohols or mixtures thereof. Examples of suitable solvents include butare not limited to methanol, isopropanol, 1-propanol, n-butanol. Thewater may be present in an amount of: about 1 to about 60 ml per mmol ofBelumosudil. In any embodiment, the process comprises:

-   -   (a) providing a mixture of Belumosudil Mesylate in water and        optionally one or more polar organic solvents, optionally with        heating,    -   (b) optionally stirring the mixture, optionally at elevated        temperature;    -   (c) optionally cooling the mixture;    -   (d) optionally stirring the cooled mixture; and    -   (e) optionally isolating crystalline form M2 of Belumosudil        Mesylate from the mixture.

In any of the embodiments of the process, the mixture in step (a) may beprepared by:

-   -   (i) providing a mixture of Belumosudil free base in water or a        mixture of water and at least one polar organic solvent;    -   (ii) combining the mixture with Methanesulfonic acid; and    -   (iii) optionally heating the mixture.

According to any embodiment of the process for preparing Form M2 ofBelumosudil Mesylate, the polar organic solvent in step (i) maypreferably comprise an alcohol or mixtures thereof. Preferably the polarorganic solvent in step (i) is selected from: methanol, isopropanol,1-propanol and n-butanol, or mixtures thereof; more preferably the polarorganic solvent in step (i) is methanol, ethanol, isopropanol,1-propanol, or n-butanol, and most preferably ethanol.

According to any embodiment of the process for preparing Form M2 ofBelumosudil Mesylate, the ratio of solvent to Belumosudil in step (i)may be: about 10 to about 40 ml per gram of Belumosudil, about 14 toabout 35 ml per gram of Belumosudil or about 16 to about 28 ml per gramof Belumosudil, or about 18 to about 24 ml per gram of Belumosudil, andoptionally about 20 ml per gram of Belumosudil. The mixture in step (i)may be a solution or a slurry.

According to any embodiment of the process for preparing Form M2 ofBelumosudil Mesylate, in step (ii), the combining of Methanesulfonicacid to Belumosudil may be in any order. Preferably, methanesulfonicacid may be added to the mixture of Belumosudil in the solvent. Theaddition may be carried out portion-wise or dropwise. TheMethanesulfonic acid is optionally added in an amount of: about 0.7 toabout 1.5 molar equivalents, about 0.9 to about 1.3 molar equivalents,about 1.0 to about 1.2 molar equivalents, or about 1.1 molar equivalentsrelative to Belumosudil. Preferably, step (ii) comprises addingMethanesulfonic acid, to the mixture of Belumosudil and solvent.

In step (iii) of the process for preparing Belumosudil Form M2, themixture may be optionally heated. The heating may be to a temperature ofabout 30° C. to about 70° C., about 40° C. to about 60° C., about 45° C.to about 55° C., or about 50° C. The heating may take place over anysuitable period of time to form a solution of Belumosudil Mesylate.

Alternatively, in the process for preparing Belumosudil Form M2according to any aspect or embodiment of the invention, the mixture instep (a) may be prepared by a process comprising:

-   -   (i-b) combining Belumosudil Mesylate with a polar organic        solvent, optionally with heating to produce a solution; and    -   (ii-b) adding water as antisolvent.

According to any embodiment of the process for preparing Form M2 ofBelumosudil Mesylate. The polar organic solvent in step (i-b) ispreferably selected from the group consisting of TFE, DMSO and ormixtures thereof. Particularly, the solvent is selected from the groupconsisting of TFE and DMSO. The ratio of polar organic solvent in step(i-b) is preferably about 5 ml to 60 ml, about 7 ml to about 50 ml,about 10 ml to about 45 ml, or about 10 ml to about 40 ml, per gram ofBelumosudil Mesylate.

Alternatively, in the process for preparing Belumosudil Form M2according to any aspect or embodiment of the invention, the mixture instep (a) may be prepared by a process comprising: (i-c) combiningBelumosudil Mesylate with water to produce a slurry. Preferably, theBelumosudil Mesylate is Form M1 as described according to any aspect orembodiment herein. Preferably, the ratio of water step (i-c) ispreferably about 10 ml to 60 ml, about 20 ml to about 50 ml, about 30 mlto about 45 ml, or about 40 ml, per gram of Belumosudil Mesylate.

In any embodiment of the process, step (b) is carried out. Step (b) ispreferably carried out under heating, preferably at a temperature of:about 30° C. to about 80° C., about 40° C. to about 75° C., about 45° C.to about 70° C., about 45° C. to about 65° C., about 45° C. to about 65°C., about 48° C. to about 62° C., or about 50° C. to about 60° C. Thestirring may be carried out for any suitable period of time.

In any embodiment of the process for preparing Form M2, step (c) iscarried out. Step (c) preferably comprises cooling the mixture to roomtemperature.

In any embodiment of the process for preparing Form M2, step (d) may becarried out. The stirring may be for any suitable time to prepare FormM2.

In any embodiment of the process for preparing crystalline BelumosudilMesylate Form M2, step (e) may be carried out by any suitable method,for example by filtration, decantation or by centrifuge. Preferably theisolation of the solid is by filtration or by centrifuge, and morepreferably by centrifuge.

In any embodiment the process may further comprise washing and/or dryingsteps.

The present disclosure includes a crystalline polymorph of BelumosudilMesylate, designated form M3. The crystalline Form M3 of BelumosudilMesylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 8 ; an X-ray powder diffraction pattern having peaks at 7.3,14.6, 16.6, 17.5 and 19.6 degrees 2-theta±0.2 degrees 2-theta; andcombinations of these data.

Crystalline Form M3 of Belumosudil Mesylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 7.3, 14.6, 16.6,17.5 and 19.6 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 12.9, 13.7,19.0, 20.6 and 26.0 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form M3 of Belumosudil Mesylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 7.3,12.9, 13.7, 14.6, 16.6, 17.5, 19.0, 19.6, 20.6 and 26.0 degrees2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form M3 ofBelumosudil Mesylate is isolated.

Crystalline Form M3 of Belumosudil Mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 7.3, 14.6, 16.6, 17.5 and 19.6degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.8 , and combinations thereof.

The present disclosure includes a crystalline polymorph of BelumosudilMesylate, designated form M4. The crystalline Form M4 of BelumosudilMesylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 11 ; an X-ray powder diffraction pattern having peaks at 7.5,15.0, 17.9, 21.8 and 22.6 degrees 2-theta±0.2 degrees 2-theta; andcombinations of these data.

Crystalline Form M4 of Belumosudil Mesylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 7.5, 15.0, 17.9,21.8 and 22.6 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 11.3, 17.4,20.9, 24.2 and 29.2 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form M4 of Belumosudil Mesylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 7.5,11.3, 15.0, 17.4, 17.9, 20.9, 21.8, 22.6, 24.2 and 29.2 degrees2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form M4 ofBelumosudil Mesylate is isolated.

Crystalline Form M4 of Belumosudil Mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 7.5, 15.0, 17.9, 21.8 and 22.6degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.11 , and combinations thereof.

The present disclosure includes a crystalline polymorph of BelumosudilMesylate, designated form M5. The crystalline Form M5 of BelumosudilMesylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 12 ; an X-ray powder diffraction pattern having peaks at 6.2,15.7, 18.4, 19.2 and 25.1 degrees 2-theta±0.2 degrees 2-theta; andcombinations of these data.

Crystalline Form M5 of Belumosudil Mesylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 6.2, 15.7, 18.4,19.2 and 25.1 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 17.8, 21.6,21.9, 24.7, 25.9 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form M5 of Belumosudil Mesylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 6.2,15.7, 17.8, 18.4, 19.2, 21.6, 21.9, 24.7, 25.1 and 25.9 degrees2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form M5 ofBelumosudil Mesylate is isolated.

Crystalline Form M5 of Belumosudil Mesylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 6.2, 15.7, 18.4, 19.2 and 25.1degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.12 , and combinations thereof.

The present disclosure includes a crystalline polymorph of BelumosudilBesylate, designated form BS1. The crystalline Form BS1 of BelumosudilBesylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 13 ; an X-ray powder diffraction pattern having peaks at 6.6,12.5, 14.9, 17.0 and 20.1 degrees 2-theta±0.2 degrees 2-theta; a solidstate ¹³C NMR spectrum with characteristic peaks at 158.9, 146.8, 134.3,121.3 and 117.6 ppm±0.2 ppm; a solid state ¹³C NMR spectrum having thefollowing chemical shift absolute differences from reference peak at169.6 ppm±1 ppm: 10.7, 22.8, 35.3, 48.3 and 52.0 ppm±0.1 ppm; a solidstate ¹³C NMR spectrum substantially as depicted in any of FIGS. 22, 23and 24 and combinations of these data.

Crystalline Form BS1 of Belumosudil Besylate may be furthercharacterized by an X-ray powder diffraction pattern having peaks at6.6, 12.5, 14.9, 17.0 and 20.1 degrees 2-theta±0.2 degrees 2-theta, andalso having any one, two, three, four or five additional peaks selectedfrom 11.6, 17.6, 18.2, 21.7 and 25.1 degrees 2-theta±0.2 degrees2-theta.

Crystalline form BS1 of Belumosudil Besylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 6.6,11.6, 12.5, 14.9, 17.0, 17.6, 18.2, 20.1, 21.7 and 25.1 degrees2-theta±0.2 degrees 2-theta.

Crystalline form BS1 of Belumosudil Besylate may be an anhydrous form,as can be determined by TGA. In certain embodiment, the presentdisclosure comprises crystalline form BS1 of Belumosudil Besylate having0.5% w/w or less, or 0.2% w/w or less, or 0.1 wt % or less, of totalresidual solvent. According to any aspect or embodiment as describedherein, crystalline form BS1 of Belumosudil Besylate may contain 0.5%w/w or less, or 0.2% w/w or less, or 0.1 wt % or less, of total residualsolvent. The residual organic solvent may be one or more polar solvents,preferably water, alcohols (particularly C₁₋₄ alcohols, especiallyethanol, methanol, isopropanol, 1-propanol, or n-butanol), and mostpreferably the residual organic solvent may be ethanol. Particularly,crystalline form BS1 of Belumosudil Besylate according to any aspect orembodiment of the disclosure may contain 0.5% w/w or less, or 0.2 w/w orless, or 0.1 wt % or less, of ethanol.

In one embodiment of the present disclosure, crystalline Form BS1 ofBelumosudil Besylate is isolated. Particularly, crystalline form BS1 ofBelumosudil Besylate according to any aspect or embodiment of thedisclosure may be isolated.

In any aspect or embodiment of the present disclosure, crystalline FormBS1 of Belumosudil Mesylate is non-hygroscopic. Particularly, Form BS1of Belumosudil Mesylate according to any aspect or embodiment ispolymorphically stable at up to 100% relative humidity at roomtemperature for at least 7 days.

Crystalline Form BS1 of Belumosudil Besylate may be characterized byeach of the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 6.6, 12.5, 14.9, 17.0 and 20.1degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.13 , and combinations thereof.

Crystalline form BS1 of Belumosudil Besylate may be prepared bycrystallisation from a mixture comprising Belumosudil Besylate and apolar solvent such as ethanol. In any aspect or embodiment, the processcomprises:

-   -   (a) providing a mixture of Belumosudil Besylate in one or more        polar solvents;    -   (b) optionally stirring the mixture, optionally at elevated        temperature;    -   (c) optionally cooling the mixture; and    -   (d) optionally isolating crystalline form BS1 of Belumosudil        Besylate from the mixture.

In any of the embodiments of the process for preparing Form BS1, themixture in step (a) may be prepared by:

-   -   (i) providing a mixture of Belumosudil free base (preferably        Form B1 as described herein) in a polar solvent; and    -   (ii) combining the mixture with Benzenesulfonic acid.

In any of the embodiment of the process for preparing Form BS1, thepolar solvent in step (i) is preferably an alcohol (particularly C₁₋₄alcohols, especially ethanol, methanol, isopropanol, 1-propanol, orn-butanol). Preferably the polar solvent comprises ethanol orisopropanol and more preferably the polar solvent is ethanol. In step(i), the ratio of solvent to Belumosudil may be: about 10 to about 40 mlper gram of Belumosudil, about 14 to about 35 ml per gram of Belumosudilor about 16 to about 28 ml per gram of Belumosudil, or about 18 to about24 ml per gram of Belumosudil, and optionally about 20 ml per gram ofBelumosudil. The mixture may be a solution or a slurry.

In any aspect or embodiment of the process for preparing Form BS1, step(ii) comprises combining Benzenesulfonic acid to Belumosudil. Thecombining may be in any order. Preferably, benzenesulfonic acid may beadded to the mixture of Belumosudil in the solvent. The addition may becarried out portion-wise or dropwise. The Benzenesulfonic acid isoptionally added in an amount of: about 0.7 to about 1.5 molarequivalents, about 0.9 to about 1.3 molar equivalents, about 1.0 toabout 1.2 molar equivalents, or about 1.1 molar equivalents relative toBelumosudil. Preferably, step (ii) comprises adding Benzenesulfonic acidto the mixture of Belumosudil and polar solvent.

Alternatively, in any of the embodiments of the process for preparingForm BS1, the mixture in step (a) may be prepared by combiningBelumosudil Besylate with a polar solvent. Preferably the polar solventis an alcohol (particularly C₁₋₄ alcohols, especially ethanol, methanol,isopropanol, 1-propanol, or n-butanol), and most preferably the polarsolvent is ethanol.

In any embodiment of the process for preparing form BS1, step (b) iscarried out, preferably by stirring at room temperature, more preferablyat a temperature of: about 30° C. to about 70° C., about 40° C. to about60° C., about 45° C. to about 55° C., or about 50° C. Preferably, thestirring is carried out at a temperature. The stirring may be carriedout for any suitable time to form Belumosudil Besylate Form BS1.Typically, the stirring may be carried out over a period of about 10minutes to about 2 hours, about 20 minutes to about 1 hour, or about 45minutes.

In any embodiment of the process for preparing form BS1, step (c) iscarried out, preferably wherein the cooling is to room temperature.

In any embodiment of the process for preparing form BS1, step (d) may becarried out by any suitable method, for example by filtration,decantation or by centrifuge. Preferably the isolation of the solid isby filtration or by centrifuge, and more preferably by centrifuge.

In any embodiment the process for preparing from BS1 may furthercomprise washing and/or drying steps.

The present disclosure includes a crystalline polymorph of BelumosudilTosylate, designated form T1. The crystalline Form T1 of BelumosudilTosylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 14 ; an X-ray powder diffraction pattern having peaks at 6.2,12.3, 14.1, 17.7 and 18.4 degrees 2-theta±0.2 degrees 2-theta; a solidstate ¹³C NMR spectrum with characteristic peaks at 152.6, 143.4, 132.3,125.3 and 119.8 ppm±0.2 ppm; a solid state ¹³C NMR spectrum having thefollowing chemical shift absolute differences from reference peak at168.6 ppm±1 ppm: 16.0, 25.2, 36.3, 43.3 and 48.8 ppm±0.1 ppm; a solidstate ¹³C NMR spectrum substantially as depicted in any of FIGS. 26, 27and 28 ; and combinations of these data.

Crystalline Form T1 of Belumosudil Tosylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 6.2, 12.3, 14.1,17.7 and 18.4 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 9.9, 14.5,16.7, 21.5 and 24.6 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form T1 of Belumosudil Tosylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 6.2,9.9, 12.3, 14.1, 14.5, 16.7, 17.7, 18.4, 21.5 and 24.6 degrees2-theta±0.2 degrees 2-theta.

Crystalline form T1 of Belumosudil Tosylate may be an anhydrous form, ascan be determined by TGA. In certain embodiment, the present disclosurecomprises crystalline form T1 of Belumosudil Tosylate having 0.5% w/w orless, or 0.2% w/w or less, or 0.1 wt % or less, of total residualsolvent. The residual solvent may be one or more polar solvents,preferably water and/or alcohols (particularly C₁₋₄ alcohols, especiallyethanol, methanol, isopropanol, 1-propanol, or n-butanol), and mostpreferably the residual organic solvent may be methanol. Particularly,crystalline form T1 of Belumosudil Tosylate according to any aspect orembodiment of the disclosure may contain to 0.5% w/w or less, or 0.2%w/w or less, or 0.1 wt % or less, of methanol.

In one embodiment of the present disclosure, crystalline Form T1 ofBelumosudil Tosylate is isolated. Particularly, crystalline form T1 ofBelumosudil Tosylate according to any aspect or embodiment of thedisclosure may be isolated.

In any aspect or embodiment of the present disclosure, crystalline FormT1 of Belumosudil Mesylate is non-hygroscopic. Particularly, Form T1 ofBelumosudil Mesylate according to any aspect or embodiment ispolymorphically stable at up to 100% relative humidity at roomtemperature for at least 7 days.

Crystalline Form T1 of Belumosudil Tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 6.2, 12.3, 14.1, 17.7 and 18.4degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.14 , and combinations thereof.

Crystalline form T1 of Belumosudil Tosylate may be prepared bycrystallisation from a mixture comprising Belumosudil Tosylate and oneor more polar solvents such as alcohols. Preferably, the solvent ismethanol. In any embodiment, the process comprises:

-   -   (a) providing a mixture of Belumosudil Tosylate in one or more        polar solvents, preferably comprising methanol;    -   (b) optionally stirring the mixture, optionally at elevated        temperature;    -   (c) optionally cooling the mixture; and    -   (d) optionally isolating crystalline form T1 of Belumosudil        Tosylate from the mixture.

In any of the embodiments of the process, the mixture in step (a) may beprepared by:

(i) providing a mixture of Belumosudil free base in a polar solvent; and

(ii) combining the mixture with Toluenesulfonic acid.

Preferably, the process for preparing Form T1 of Belumosudil Tosylateaccording to any embodiment described herein is carried out in theabsence of water or substantially in the absence of water, particularly2 wt % or less, 1 wt % or less, 0.5 wt % or less, 0.2 wt % or less, or0.1 wt % or less of water.

In any aspect or embodiment of the process for preparing Form T1, thepolar solvent is preferably an alcohol (particularly C₁₋₄ alcohols,especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol),and most preferably the polar solvent is methanol. In step (i), theratio of solvent to Belumosudil may be: about 10 to about 40 ml per gramof Belumosudil, about 14 to about 35 ml per gram of Belumosudil or about16 to about 28 ml per gram of Belumosudil, or about 18 to about 24 mlper gram of Belumosudil, and optionally about 20 ml per gram ofBelumosudil. The mixture may be a solution or a slurry

In step (ii), combining of Toluenesulfonic acid to Belumosudil may be inany order. Preferably, Toluenesulfonic acid may be added to the mixtureof Belumosudil in the solvent. The addition may be carried outportion-wise or dropwise. The Toluenesulfonic acid is optionally addedin an amount of: about 0.7 to about 1.5 molar equivalents, about 0.9 toabout 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents,or about 1.1 molar equivalents relative to Belumosudil. Preferably, step(ii) comprises adding Toluenesulfonic acid, to the mixture ofBelumosudil and solvent.

Alternatively, in any of the embodiments of the process for preparingForm T1, the mixture in step (a) may be prepared by combiningBelumosudil Tosylate with a polar solvent. Preferably the polar solventis an alcohol (particularly C₁₋₄ alcohols, especially ethanol, methanol,isopropanol, 1-propanol, or n-butanol), and most preferably the polarsolvent is methanol.

In any embodiment of the process for preparing Form T1, step (b) iscarried out, preferably by stirring at a temperature of: about 30° C. toabout 70° C., about 40° C. to about 60° C., about 45° C. to about 55°C., or about 50° C. The stirring may be carried out for any suitabletime.

In any embodiment of the process for preparing form T1, step (c) iscarried out, preferably wherein the cooling is to room temperature.

In any embodiment of the process for preparing form T1, step (d) may becarried out by any suitable method, for example by filtration,decantation or by centrifuge. Preferably the isolation of the solid isby filtration or by centrifuge, and more preferably by centrifuge.

In any embodiment of the process for preparing Form T1, the process mayfurther comprise washing and/or drying steps.

The present disclosure includes a crystalline polymorph of BelumosudilTosylate, designated form T2. The crystalline Form T2 of BelumosudilTosylate may be characterized by data selected from one or more of thefollowing: an X-ray powder diffraction pattern substantially as depictedin FIG. 15 ; an X-ray powder diffraction pattern having peaks at 5.1,15.7, 16.4, 19.7 and 23.7 degrees 2-theta±0.2 degrees 2-theta; a solidstate ¹³C NMR spectrum with characteristic peaks at 141.7, 140.2, 131.1,125.9 and 124.2 ppm±0.2 ppm; a solid state ¹³C NMR spectrum having thefollowing chemical shift absolute differences from reference peak at166.3 ppm±1 ppm: 24.6, 26.1, 35.2, 40.4 and 42.1 ppm±0.1 ppm; a solidstate ¹³C NMR spectrum substantially as depicted in any of FIGS. 30, 31and 32 ; and combinations of these data.

Crystalline Form T2 of Belumosudil Tosylate may be further characterizedby an X-ray powder diffraction pattern having peaks at 5.1, 15.7, 16.4,19.7 and 23.7 degrees 2-theta±0.2 degrees 2-theta, and also having anyone, two, three, four or five additional peaks selected from 13.7, 14.2,14.6, 19.1 and 23.0 degrees 2-theta±0.2 degrees 2-theta.

Crystalline form T2 of Belumosudil Tosylate may be alternativelycharacterized by X-ray powder diffraction pattern having peaks at 5.1,13.7, 14.2, 14.6, 15.7, 16.4, 19.1, 19.7, 23.0 and 23.7 degrees2-theta±0.2 degrees 2-theta.

Crystalline form T2 of Belumosudil Tosylate may be an anhydrous form, ascan be determined by TGA. In certain embodiment, the present disclosurecomprises crystalline form T2 of Belumosudil Tosylate having 1% w/w orless, or 0.5% w/w or less or 0.2% w/w or less, or 0.1 wt % or less, oftotal residual solvent. The residual solvent may be one or more polarsolvents, preferably water or alcohols (particularly C₁₋₄ alcohols,especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol),and most preferably the residual organic solvent may be water and/orethanol. Particularly, crystalline form T2 of Belumosudil Tosylateaccording to any aspect or embodiment of the disclosure may contain 0.5%w/w or less, or 0.2% w/w or less, or 0.1 wt % or less, of ethanol. Inone embodiment of the present disclosure, crystalline Form T2 ofBelumosudil Tosylate is isolated. Particularly, crystalline form T2 ofBelumosudil Tosylate according to any aspect or embodiment of thedisclosure may be isolated.

In any aspect or embodiment of the present disclosure, crystalline FormT2 of Belumosudil Mesylate is non-hygroscopic. Particularly, Form T2 ofBelumosudil Mesylate according to any aspect or embodiment ispolymorphically stable at up to 100% relative humidity at roomtemperature for at least 7 days.

Crystalline Form T2 of Belumosudil Tosylate may be characterized by eachof the above characteristics alone/or by all possible combinations,e.g., an XRPD pattern having peaks at 5.1, 15.7, 16.4, 19.7 and 23.7degrees 2-theta±0.2 degrees 2-theta; an XRPD pattern as depicted in FIG.15 , and combinations thereof.

Crystalline form T2 of Belumosudil Tosylate may be prepared bycrystallisation from a mixture comprising Belumosudil Tosylate and oneor more polar solvent such as water. In any embodiment, the processcomprises:

-   -   (a) providing a mixture of Belumosudil Tosylate in one or more        polar solvent;    -   (b) optionally stirring the mixture, optionally at elevated        temperature;    -   (c) optionally cooling to room temperature; and    -   (d) optionally isolating crystalline form T2 of Belumosudil        Mesylate from the mixture.

In any of the embodiments of the process for preparing Form T2, themixture in step (a) may be prepared by:

-   -   (i) providing a mixture of Belumosudil free base (preferably        Form B1 as described herein) in a polar solvent, preferably        comprising water and/or ethanol; and    -   (ii) combining the mixture with Toluenesulfonic acid, optionally        at elevated temperature; and    -   (iii) optionally adding a polar solvent.

In any aspect or embodiment of the process for preparing Form T2, thepolar solvent in step (i) preferably comprises water, and morepreferably the polar solvent in step (i) water. In step (i), the ratioof solvent to Belumosudil may be: about 10 to about 40 ml per gram ofBelumosudil, about 14 to about 35 ml per gram of Belumosudil or about 16to about 28 ml per gram of Belumosudil, or about 18 to about 24 ml pergram of Belumosudil, about 20 to about 30, and optionally about 20 mlper gram of Belumosudil. The mixture may be a solution or a slurry.

In any aspect or embodiment of the process for preparing Form T2, step(ii) comprises combining Toluenesulfonic acid to Belumosudil in anyorder. Preferably, Toluenesulfonic acid may be added to the mixture ofBelumosudil in the solvent. The addition may be carried out portion-wiseor dropwise. The Toluenesulfonic acid is optionally added in an amountof: about 0.7 to about 1.5 molar equivalents, about 0.9 to about 1.3molar equivalents, about 1.0 to about 1.2 molar equivalents, or about1.1 molar equivalents relative to Belumosudil. Preferably, step (ii)comprises adding Toluenesulfonic acid, to the mixture of Belumosudil andsolvent.

In any aspect or embodiment of the process for preparing Form T2, instep (iii), the polar solvent is preferably selected from the groupconsisting of methanol, ethanol, isopropanol, 1-propanol, and n-butanol.More preferably, the polar solvent in step (iii) is ethanol. In step(iii), the ratio of total solvent to Belumosudil may be from: about 20to about 50 ml, about 20 to about 40 ml, about 22 to about 35 ml, orabout 25 ml, per gram of Belumosudil.

Alternatively, in any of the embodiments of the process for preparingForm T2, the mixture in step (a) may be prepared by combiningBelumosudil Tosylate with one or more polar solvents. Preferably thepolar solvent is water and/or an alcohol (particularly C₁₋₄ alcohols,especially ethanol, methanol, isopropanol, 1-propanol, or n-butanol).Preferably, the polar solvent is water and ethanol.

In any embodiment of the process for preparing Form T2, step (b) iscarried out, preferably by stirring at a temperature of: about 30° C. toabout 70° C., about 40° C. to about 60° C., about 45° C. to about 55°C., or about 50° C. The stirring may be carried out for any suitabletime. Typically, the stirring may be carried out over a period of about10 minutes to about 2 hours, about 20 minutes to about 1 hour, or about50 minutes.

In any embodiment of the process for preparing Form T2, the mixture maybe cooled, preferably to room temperature, and step (d) may be carriedout by any suitable method, for example by filtration, decantation or bycentrifuge. Preferably the isolation of the solid is by filtration or bycentrifuge, and more preferably by centrifuge.

In any embodiment the process may further comprise washing and/or dryingsteps.

The above crystalline polymorphs of Belumosudil or salts thereof,including Belumosudil Mesylate, Belumosudil Tosylate and/or BelumosudilBesylate can be used to prepare other crystalline polymorphs ofBelumosudil, Belumosudil salts and their solid state forms.

The present disclosure encompasses a process for preparing other solidstate forms of Belumosudil, Belumosudil salts and their solid stateforms thereof. The process includes preparing any one of the solid stateforms of Belumosudil or salts thereof by the processes of the presentdisclosure, and converting that salt to said other Belumosudil salt. Theconversion can be done, for example, by a process including basifyingany one or a combination of the above described salts such asBelumosudil Mesylate Belumosudil Tosylate and/or Belumosudil Besylateand/or solid state forms thereof, and reacting the obtained Belumosudilbase with an appropriate acid, to obtain the corresponding salt.Alternatively, the conversion can be done by salt switching, i.e.,reacting a Belumosudil acid addition salt, with an acid having a pKawhich is lower than the pKa of the acid of the first Belumosudil acidaddition salt.

The present disclosure provides the above described crystallinepolymorphs of Belumosudil or salts thereof, including BelumosudilMesylate, Belumosudil Tosylate and/or Belumosudil Besylate for use inthe preparation of pharmaceutical compositions comprising Belumosudil,salts thereof and/or crystalline polymorphs thereof.

The present disclosure also encompasses the use of crystallinepolymorphs of Belumosudil or salts thereof, such as crystalline forms ofBelumosudil Mesylate, Belumosudil Tosylate and/or Belumosudil Besylateof the present disclosure for the preparation of pharmaceuticalcompositions of crystalline polymorph Belumosudil or salts thereof, suchas including Belumosudil Mesylate, Belumosudil Tosylate and/orBelumosudil Besylate and/or crystalline polymorphs thereof.

In any aspect or embodiment of the present disclosure, any of the solidstate forms of Belumosudil, Belumosudil Mesylate, Belumosudil Tosylateand/or Belumosudil Besylate described herein may be polymorphically pureor may be substantially free of any other solid state forms of thesubject compound (i.e., Belumosudil, Belumosudil Mesylate, BelumosudilTosylate and/or Belumosudil Besylate, respectively). In any aspect orembodiment of the present disclosure, any of the solid state forms ofBelumosudil, Belumosudil Mesylate, Belumosudil Tosylate and/orBelumosudil besylate may contain: about 20% (w/w) or less, about 10%(w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1%(w/w) or less, about 0.5% (w/w) or less, about 0.2% (w/w) or less, about0.1% (w/w) or less, or about 0%, of any other solid state forms of thesubject compound, preferably as measured by XRPD. Thus, any of thedisclosed crystalline forms of Belumosudil, Belumosudil Mesylate,Belumosudil Tosylate and/or Belumosudil besylate described herein may besubstantially free of any other solid state forms of the subjectcompound, and may contain greater than about 80% (w/w), greater thanabout 90% (w/w), greater than about 95% (w/w), greater than about 98%(w/w), greater than about 99% (w/w), or about 100% of the solid stateform of the Belumosudil, Belumosudil Mesylate, Belumosudil Tosylateand/or Belumosudil besylate.

The present disclosure includes processes for preparing the abovementioned pharmaceutical compositions. The processes include combiningany one or a combination of the crystalline polymorphs of Belumosudil orsalts thereof, of the present disclosure with at least onepharmaceutically acceptable excipient.

Pharmaceutical combinations or formulations of the present disclosurecontain any one or a combination of the solid state forms of Belumosudilor salts thereof, of the present disclosure. In addition to the activeingredient, the pharmaceutical formulations of the present disclosurecan contain one or more excipients. Excipients are added to theformulation for a variety of purposes. Preferably, the pharmaceuticalcomposition or formulation according to any aspect or embodiment of thepresent disclosure is in the form of a tablet or a capsule, morepreferably a tablet.

Diluents increase the bulk of a solid pharmaceutical composition, andcan make a pharmaceutical dosage form containing the composition easierfor the patient and caregiver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g., Avicel®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g., Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol, and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, can include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.,Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g., Explotab®), andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatcan function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present disclosure include maltol, vanillin, ethyl vanillin,menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,Belumosudil and any other solid excipients can be dissolved or suspendedin a liquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol, or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol, and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanth,xanthan gum and combinations thereof.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol, and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxyl toluene, butylated hydroxyanisole, andethylenediamine tetraacetic acid can be added at levels safe foringestion to improve storage stability.

According to the present disclosure, a liquid composition can alsocontain a buffer such as gluconic acid, lactic acid, citric acid, oracetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodiumacetate. Selection of excipients and the amounts used can be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

The solid compositions of the present disclosure include powders,granulates, aggregates, and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant, and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, in embodiments the route of administration is oral. The dosagescan be conveniently presented in unit dosage form and prepared by any ofthe methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches, and lozenges, as well as liquid syrups,suspensions, and elixirs.

The dosage form of the present disclosure can be a capsule containingthe composition, such as a powdered or granulated solid composition ofthe disclosure, within either a hard or soft shell. The shell can bemade from gelatin and optionally contain a plasticizer such as glycerinand/or sorbitol, an opacifying agent and/or colorant.

The active ingredient and excipients can be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried, and thenscreened and/or milled to the desired particle size. The granulate canthen be tableted, or other excipients can be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate, and colloidalsilica. The proper use of these and other excipients in directcompression tableting is known to those in the art with experience andskill in particular formulation challenges of direct compressiontableting.

A capsule filling of the present disclosure can include any of theaforementioned blends and granulates that were described with referenceto tableting, but they are not subjected to a final tableting step.

A pharmaceutical formulation of Belumosudil can be administered.Belumosudil may be formulated for administration to a mammal, inembodiments to a human, by injection. Belumosudil can be formulated, forexample, as a viscous liquid solution or suspension, such as a clearsolution, for injection. The formulation can contain one or moresolvents. A suitable solvent can be selected by considering thesolvent's physical and chemical stability at various pH levels,viscosity (which would allow for syringeability), fluidity, boilingpoint, miscibility, and purity. Suitable solvents include alcohol USP,benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additionalsubstances can be added to the formulation such as buffers,solubilizers, and antioxidants, among others. Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

The crystalline polymorphs of Belumosudil and the pharmaceuticalcompositions and/or formulations of Belumosudil of the presentdisclosure can be used as medicaments, in embodiments in the treatmentof Graft-Versus-Host Disease including Chronic Graft-Versus-HostDisease, Systemic Sclerosis including Diffuse Cutaneous SystemicSclerosis, Fibrosis including Idiopathic Pulmonary Fibrosis, PlaquePsoriasis, Systemic Scleroderma, and particularly ChronicGraft-Versus-Host Disease and/or Systemic Sclerosis.

The present disclosure also provides methods of treatingGraft-Versus-Host Disease including Chronic Graft-Versus-Host Disease,Systemic Sclerosis including Diffuse Cutaneous Systemic Sclerosis,Fibrosis including Idiopathic Pulmonary Fibrosis, Plaque Psoriasis,Systemic Scleroderma, and particularly Chronic Graft-Versus-Host Diseaseand/or Systemic Sclerosis by administering a therapeutically effectiveamount of any one or a combination of the crystalline polymorphs ofBelumosudil of the present disclosure, or at least one of the abovepharmaceutical compositions and/or formulations, to a subject in need ofthe treatment.

Having thus described the disclosure with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the disclosure as described and illustratedthat do not depart from the spirit and scope of the disclosure asdisclosed in the specification. The Examples are set forth to aid inunderstanding the disclosure but are not intended to, and should not beconstrued to limit its scope in any way.

Powder X-Ray Diffraction (“XRPD”) Method

For Examples 1-9 and 12-15: XRPD analysis was performed on ARL (SCINTAG)powder X-Ray diffractometer model X'TRA equipped with a solid statedetector. Copper radiation of 1.5418 Å was used. Scanning parameters:range: 2-40 degrees two-theta; scan mode: continuous scan; step size:0.05°, and a rate of 3 deg/min.

For examples 10 and 11: XRPD analysis was performed on a Bruker powderX-Ray diffractometer model D8 ADVANCE equipped with a solid statedetector. Copper radiation of 1.54060 Å was used. Scanning parameters:range: 2-40 degrees two-theta; scan mode; step size: 0.05°.

The positions of the peaks were corrected respective to the silicontheoretical peak at 28.45 degrees two theta.

Solid State ¹³C-NMR Method

Solid-state 13C NMR spectra were recorded with variable amplitude crosspolarization, magic angle spinning and high power proton decouplingusing a BRUKER Avance II+ spectrometer operating at 125 MHz andcontrolled temperature at 0° C. A probe using 4 mm o.d. zirconia rotorswas employed. The operation conditions were: contact time: 2 ms; recycledelay: 5 s; 1024 scans and spin rate of 11 kHz. Chemical shifts werereferenced via a replacement sample of glycine (carboxyl carbon chemicalshift assigned as 176.03 ppm relative to the signal oftetramethylsilane).

TGA Method

Thermogravimetric analysis was carried out Mettler Toledo TGA/DSC withthe following scanning parameters:

Heating between 25-250° C.

Heating rate: 10° C./min.

Purging with 40 ml/min N₂ flow.

Sample weight: 7-15 mg.

Crucible: 150 μL alumina Crucible with standard aluminum lid.

SEM Method

SEM micrographs were taken on Phenom Pro, scanning microscope at 10 kV,low current. Samples were sputtered with gold by Denton Desk V sputtercoater.

EXAMPLES

Preparation of Starting Materials

Belumosudil can be prepared according to methods known from theliterature, for example according to International Publication No. WO2006/105081.

Example 1: Preparation of Amorphous Belumosudil

Procedure A

Methanol (90 ml, 90V) was added to Belumosudil (1 gram, 2.21 mmol) togive a slurry. The slurry was magnetically stirred at 62° C. for 15minutes to obtain clear solution followed by mechanical filtration. Thesolution was cooled to room temperature and then was dried in spraydrier at Tin=140° C. (Tout=78° C.). The obtained solid was analyzed byX-ray powder diffraction and the XRPD pattern is presented in FIG. 1 .

Procedure B

Methanol (3.5 ml, 70V) was added to Belumosudil (50 mg, 0.11 mmol) togive slurry. The slurry was magnetically stirred at 60° C. for 15minutes to obtain clear solution followed by mechanical filtration. Theobtained clear mother-liquor was evaporated upon 50° C./300-35 mbar togive a solid. The obtained solid was characterized by X-ray powderdiffraction as Amorphous Belumosudil.

Example 2: Preparation of Crystalline Form B1 of Belumosudil

Procedure A

Acetone (7.5 ml, 250V) was added to Belumosudil (30 mg, 0.066 mmol) toobtain a clear solution. The solution was then mechanically filtered atroom temperature and allowed to slowly evaporate at this temperatureover a period of 6 days. The obtained solid was analyzed by X-ray powderdiffraction and Belumosudil crystal form B1 was obtained. The XRPDpattern is presented in FIG. 2 .

Procedure B

Ethanol (0.6 ml, 20V) was added to Amorphous Belumosudil (30 mg, 0.066mmol) to give slurry. The slurry was magnetically stirred at 50° C. overa period of 5 hours. The solid was separated by centrifuge and dried ina vacuum oven at 45° C. over a period of 20 hours to afford an off whitesolid, which was identified as Belumosudil crystalline form B1.

Example 3: Preparation of Crystalline Form B2 of Belumosudil

Procedure A

Acetonitrile (12 ml, 400V) was added to Amorphous Belumosudil (30 mg,0.066 mmol) at 80° C. to obtain clear solution. The solution was thenmechanically filtered at room temperature and allowed to slowlyevaporate at this temperature over a period of 5 days. The obtainedsolid was analyzed by XRPD and characterized as Belumosudil crystallineform B2. The XRPD pattern is presented in FIG. 3 .

Procedure B

Amorphous Belumosudil (30 mg, 0.066 mmol) was heated by TGA to 160° C.over a period of 0.5 hours. The obtained solid was analyzed by X-raypowder diffraction and identified as Belumosudil crystalline form B2.

Procedure C

Methanol (12 ml, 400V) was added to Amorphous Belumosudil (30 mg, 0.066mmol) to give a slurry at room temperature. The slurry was magneticallystirred at 50° C. over a period of 5 hours. The solid was separated bycentrifuge and dried in a vacuum oven at 45° C. over a period of 20hours. The obtained off white solid was analyzed by X-ray powderdiffraction and characterized by X-ray powder diffraction as Belumosudilcrystal form B2.

Example 4: Preparation of Crystalline Form B3 of Belumosudil

Tetrahydrofuran (5 ml, 50V) was added to Belumosudil (100 mg, 0.22 mmol)at 40° C. and stirred for 10 minutes to obtain clear solution. Thesolution was then mechanically filtered, cooled to room temperature andstirred over a period of 14 hours to afford a wet solid. The solid wasseparated by centrifuge. The obtained wet solid was analyzed by XRPD andcharacterized as Belumosudil crystalline form B3. The XRPD pattern ispresented in FIG. 4 .

Example 5: Preparation of Crystalline Form M1 of Belumosudil Mesylate

Procedure A

Ethanol (4 ml, 20V) was added to Belumosudil (200 mg, 0.44 mmol) toobtain a slurry at room temperature. Next, Methanesulfonic acid (31 μL,1.1 eq) was added drop-wise to give clear solution. The solution washeated to 50° C. and precipitation was observed. Ethanol (3 ml, 15V) wasadded to the obtained massive precipitate followed by magneticallystirring over a period of 30 minutes at 50° C. Next, the precipitate wasspontaneously cooled to room temperature. The solid was separated bycentrifuge. The obtained solid was washed twice with ethanol (400 μL,2V) and dried in a vacuum oven at 45° C. over a period of 16 hours toafford yellow solid. The obtained solid was analyzed by X-ray powderdiffraction and characterized as Belumosudil Mesylate crystal form M1.The XRPD pattern is presented in FIG. 5 .

Procedure B

DMSO (0.9 ml, 30V) was added to Belumosudil Mesylate salt (30 mg, 0.06mmol) to give slurry. The slurry was heated to 50° C. for 10 minutes toobtain complete dissolution, followed by a hot mechanical filtration.Next, ethanol as anti-solvent (2.7 ml, 100V) was added drop-wise toobtain a solid precipitate. Next, the slurry was magnetically stirred atroom temperature during 40 hours. Then, the solid was isolated bycentrifuge. The obtained wet solid was analyzed by X-ray powderdiffraction and identified as Belumosudil Mesylate crystal form M1.

Procedure C

Isopropyl alcohol (2 ml, 20V) was added to Belumosudil (100 mg, 0.2mmol) to obtain a slurry at room temperature. Next, Methanesulfonic acid(161 μL, 1.1 eq) was added drop-wise to give clear solution. Thesolution was heated to 50° C. and precipitation was observed andmagnetically stirring over a period of 30 minutes at 50° C. Next, theprecipitate was spontaneously cooled to room temperature. The solid wasseparated by centrifuge. The obtained solid was washed twice with IPA(200 μL, 2V) to afford yellow solid. The obtained solid was analyzed byX-ray powder diffraction and identified as Belumosudil Mesylate crystalform M1.

Procedure D

N-butanol (2 ml, 20V) was added to Belumosudil (100 mg, 0.2 mmol) toobtain a slurry at room temperature. Next, Methanesulfonic acid (161 μL,1.1 eq) was added drop-wise to give clear solution. The solution washeated to 50° C. and precipitation was observed and magneticallystirring over a period of 30 minutes at 50° C. Next, the precipitate wasspontaneously cooled to room temperature. The solid was separated bycentrifuge. The obtained solid was washed twice with N-butanol (200 μL,2V) to afford yellow solid. The obtained solid was analyzed by X-raypowder diffraction and identified as Belumosudil Mesylate crystal formM1.

Procedure E

1-propanol (2 ml, 20V) was added to Belumosudil (100 mg, 0.2 mmol) toobtain a slurry at room temperature. Next, Methanesulfonic acid (161 μL,1.1 eq) was added drop-wise to give clear solution. The solution washeated to 50° C. and precipitation was observed and magneticallystirring over a period of 30 minutes at 50° C. Next, the precipitate wasspontaneously cooled to room temperature. The solid was separated bycentrifuge. The obtained solid was washed twice with 1-propanol (200 μL,2V to afford yellow solid. The obtained solid was analyzed by X-raypowder diffraction and identified as Belumosudil Mesylate crystal formM1

Procedure F

2,2,2-Trifluoroethanol (0.3 ml, 10V) was added to Belumosudil Mesylatesalt (30 mg, 0.06 mmol) to give slurry. The slurry was heated to 60° C.for 10 minutes to obtain complete dissolution, followed by a hotmechanical filtration. Next, ethanol as anti-solvent (1.2 ml, 40V) wasadded drop-wise to obtain a solid precipitate. Next, the slurry wasmagnetically stirred at room temperature during 17 hours. Then, thesolid was isolated by centrifuge. The obtained wet solid was analyzed byX-ray powder diffraction and identified as Belumosudil Mesylate crystalform M1.

Example 6: Preparation of Crystalline Form B4 of Belumosudil

Procedure A

Methanol (0.6 ml, 20V) was added to Belumosudil form B1 (30 mg, 0.066mmol) to obtain a slurry. The slurry was then magnetically stirred at50° C. for 5 hours. Then, the slurry was cooled to room temperature andmagnetically stirred for 16 hours. The solid was then isolated at roomtemperature by centrifuge. The obtained wet solid was dried in a vacuumoven at 45° C. over a period of 18 hours to afford an off white solidwhich was characterized by X-ray powder diffraction and the XRPD patternis presented in FIG. 6 .

Procedure B

Acetonitrile:MeOH (0.75 ml, 25V, 1:1 eq) was added to B1 (50 mg, 0.11mmol) to give a slurry. The slurry was magnetically stirred at roomtemperature for a period of 1 week. The solid was then isolated at roomtemperature by centrifuge. The obtained wet solid was characterized byX-ray powder diffraction as Belumosudil crystal form B4.

Example 7: Preparation of Crystalline Form M2 of Belumosudil Mesylate

Procedure A

Water (2 ml, 20V) was added to Form B1 (100 mg, 0.22 mmol) to obtain aslurry at room temperature. Next, Methanesulfonic acid (16 μL, 1.1 eq)was added drop-wise to give a slurry. The slurry was heated to 50° C.over a period of 45 minutes to obtain a clear solution. Next, thesolution was spontaneously cooled to room temperature and a precipitatewas observed. The obtained solid was isolated using a centrifuge. Theisolated solid was washed twice with water (0.2 ml, 2V) and dried in avacuum oven at 45° C. over a period of 18 hours to afford a yellowsolid. The obtained solid was analyzed by X-ray powder diffraction andthe XRPD pattern is presented in FIG. 7 .

Procedure B

A Water:Ethanol (2 ml, 20V, 1:3) mixture was added to Form B1 (100 mg,0.22 mmol) to obtain a slurry at room temperature. Next, Methanesulfonicacid (16 μL, 1.1 eq) was added drop-wise to give a slurry. The slurrywas heated to 50° C. over a period of 45 minutes to obtain a clearsolution. Next, the solution was spontaneously cooled to roomtemperature and a precipitate was observed. The obtained solid wasisolated using a centrifuge. The isolated solid was washed twice withwater:ethanol (2.2 ml, 22V, 1:3) and dried in a vacuum oven at 45° C.over a period of 18 hours to afford yellow solid. The obtained solid wasanalyzed by X-ray powder diffraction and identified as BelumosudilMesylate crystal form M2.

Procedure C

Water (2 ml, 40V) was added to Belumosudil Mesylate salt form M1 (50 mg,0.11 mmol) to give a slurry. The slurry was magnetically stirred at 60°C. over a period of 1 week. Then, the solid was isolated at roomtemperature by centrifuge. The obtained wet solid was analyzed by X-raypowder diffraction and identified as Belumosudil Mesylate crystal formM2.

Procedure D

DMSO (2 ml, 40V) was added to Belumosudil Mesylate salt form M1 (50 mg,0.11 mmol) to give a slurry. The slurry was heated to 50° C. for 10minutes to obtain complete dissolution, followed by a hot mechanicalfiltration. The solution was spontaneously cooled to room temperatureand magnetically stirred for 5 days. Next, cold water as anti-solvent (5ml, 100V, 4° C.) was added drop-wise to obtain a solid precipitate.Next, the slurry was magnetically stirred at room temperature during 18hours. Then, the solid was isolated by centrifuge. The obtained wetsolid was analyzed by X-ray powder diffraction and identified asBelumosudil Mesylate crystal form M2.

Procedure E

2,2,2-Trifluoroethanol (0.3 ml, 10V) was added to Belumosudil Mesylatesalt (30 mg, 0.06 mmol) to give slurry. The slurry was heated to 60° C.for 10 minutes to obtain complete dissolution, followed by a hotmechanical filtration. Next, water as anti-solvent (1.2 ml, 40V) wasadded drop-wise to obtain a solid precipitate. Next, the slurry wasmagnetically stirred at room temperature during 17 hours. Then, thesolid was isolated by centrifuge. The obtained wet solid was analyzed byX-ray powder diffraction and identified as Belumosudil Mesylate crystalform M2.

Example 8: Preparation of Crystalline Form M3 of Belumosudil Mesylate

Procedure A

Belumosudil Mesylate salt form M2 (prepared according to procedure C ofexample 7) was dried in a vacuum oven at 200° C. over a period of 4hours to afford a yellow solid. The obtained solid was characterized byX-ray powder diffraction as Belumosudil Mesylate crystal form M3.

Example 9: Preparation of Crystalline Form B5 of Belumosudil

Procedure A

2,2,2-Trifluoroethanol (TFE) (0.6 ml, 50V) was added to Belumosudil(12.5 mg, 0.03 mmol) to obtain clear solution. The solution was thenmagnetically stirred at 70° C. for 1 hour. Then, the solution was cooledto 4° C. at a rate of 20° C. every 10 minutes and a massive precipitatewas observed. Additional TFE (0.1 ml, 10V) was added to give a slurry.Next, the solid was isolated using a centrifuge. Next, the motherliqueur was left for slow crystallization at 4° C. for 20 days. Theobtained wet solid was filtered by Buchner and the solid wascharacterized by X-ray powder diffraction as Belumosudil crystal form B5and the XRPD pattern is presented in FIG. 9 .

Example 10: Preparation of Amorphous Belumosudil Mesylate

Procedure A

Methanol (286 ml, 220 V) was added to Belumosudil Mesylate Form M1 (1.3grams, 2.4 mmol) to give slurry. The slurry was magnetically stirred at62° C. for 45 minutes to obtain a clear solution followed by mechanicalfiltration. The solution was cooled to room temperature and then wasdried in spray drier at Tin=140° C. (Tout=63° C.). The obtained solidwas analyzed by X-ray powder diffraction and identified as AmorphousBelumosudil Mesylate and the XRPD pattern is presented in FIG. 10 .

Example 11: Preparation of Form M4 of Belumosudil Mesylate

Procedure A

2, 2, 2-Trifluoroethanol (TFE) (0.7 ml, 7V) was added to BelumosudilMesylate form M1 (100 mg, 0.2 mmol) to obtain a clear solution. Theclear solution was mechanically filtered and was added to Heptane (0.8ml, 8V) that was precooled to 4° C. to obtain two phases. The solutionwas stirred at 4° C. for 4 days. Then, the mixture was seeded withBelumosudil Mesylate M3 (about 1 wt %) and after stirring for 1 day asolid precipitate was obtained. Next, the precipitate was isolated bycentrifuge and dried in a vacuum oven at 45° C. over a period of 18hours to afford yellow solid. The obtained solid was analyzed by X-raypowder diffraction and the XRPD pattern is presented in FIG. 11 .

Procedure B

TFE (0.7 ml, 7V) was added to Belumosudil Mesylate form M1 (100 mg, 0.2mmol) to obtain a clear solution. The clear solution was mechanicallyfiltered and was added to Heptane (0.8 ml, 8V) that was precooled to 4°C. to obtain two phases. Then, the mixture was seeded with BelumosudilMesylate form M4 (about 1 wt %) and after stirring for 1 day solidprecipitate was obtained. Next, the precipitate was isolated bycentrifuge and dried in a vacuum oven at 45° C. over a period of 18hours to afford a yellow solid. The obtained solid was analyzed by X-raypowder diffraction and identified as Belumosudil Mesylate crystal formM4.

Procedure C

TFE (0.7 ml, 7V) was added to Belumosudil Mesylate form M1 (100 mg, 0.2mmol) to obtain a clear solution. The clear solution was mechanicallyfiltered and was added to cyclopentylmethyl ether (0.8 ml, 8V) that wasprecooled to 4° C. Then, the mixture was seeded with BelumosudilMesylate form M4 (about 1 wt %) and after stirring for 18 hours a solidprecipitate was obtained. Next, the precipitate was isolated bycentrifuge and dried in a vacuum oven at 45° C. over a period of 18hours to afford yellow solid. The obtained solid was analyzed by X-raypowder diffraction and identified as Belumosudil Mesylate crystal formM4.

Procedure D

TFE (0.7 ml, 7V) was added to Belumosudil Mesylate form M1 (100 mg, 0.2mmol) to obtain a clear solution. The clear solution was added tocyclopentylmethyl ether (0.8 ml, 8V) that was precooled to 4° C. andmassive slurry was obtained. Next, cyclopentylmethyl ether (0.4 ml, 4V)was added to obtain slurry. Then, the mixture was seeded with NaCl(about 1 wt %) and after stirring for 1 hour precipitate was obtained.Next, the precipitate was isolated by centrifuge and dried in a vacuumoven at 45° C. over a period of 18 hours to afford yellow solid. Theobtained solid was analyzed by X-ray powder diffraction and identifiedas Belumosudil Mesylate crystal form M4.

Example 12: Preparation of Form M5 of Belumosudil Mesylate

Procedure A

DMSO (9 ml, 30V) was added to Belumosudil Mesylate form M1 (300 mg, 0.6mmol) to obtain a clear solution. Next, the clear solution was added tocyclopentylmethyl ether (9 ml, 30V) containing seeds of BelumosudilMesylate form M4 (about 1 wt %) that was precooled to about 4° C., thenadditional cyclopentylmethyl ether (18 ml, 60V) and seeds of BelumosudilMesylate form M4 (about 1 wt %) were added and after 10 minutes someprecipitant was observed. The mixture was stirred for a period of 18hours at about 4° C. and massive precipitate was obtained. Next, theprecipitate was isolated by centrifuge and dried in a vacuum oven at 45°C. over a period of 18 hours to afford yellow solid. The obtained solidwas analyzed by X-ray powder diffraction and the XRPD pattern ispresented in FIG. 12 .

Example 13: Preparation of Form BS1 of Belumosudil Besylate

Procedure A

Ethanol (10 ml, 20V) was added to Belumosudil form B1 (500 mg, 1.1 mmol)to obtain a slurry at room temperature. Next, Benzenesulfonic acid(192.3 mg, 1.1 eq) was added and the slurry was heated to 50° C. over aperiod of 45 minutes with stirring. Next, the slurry was spontaneouslycooled to room temperature and the obtained solid was isolated usingcentrifuge. The isolated solid was dried in a vacuum oven at 45° C. overa period of 18 hours to afford yellow solid. The obtained solid wasanalyzed by X-ray powder diffraction and the XRPD pattern is presentedin FIG. 13 .

Example 14: Preparation of Form T1 of Belumosudil Tosylate

Procedure A

Methanol (2 ml, 20V) was added to Belumosudil form B1 (100 mg, 0.22mmol) and heated to 50° C. to obtain a slurry. Next, p-toluenesulfonicacid (46.2 mg, 1.1 eq) was added and a clear solution was obtained.After stirring for 10 minutes at 50° C. precipitation was observed. Thesolution was stirred at 50° C. over a period of 45 minutes. Next, thesolution was spontaneously cooled to room temperature and massiveprecipitation was observed. The obtained solid was isolated usingcentrifuge and washed once with Methanol (200 μL, 2V). The solid wasdried in a vacuum oven at 45° C. over a period of 18 hours to affordyellow solid. The obtained solid was analyzed by X-ray powderdiffraction and the XRPD pattern is presented in FIG. 14 .

Example 15: Preparation of Form T2 of Belumosudil Tosylate

Procedure A

Water (1 ml, 20V) was added to Belumosudil form B1 (50 mg, 0.11 mmol)and heated to 50° C. to obtain slurry. Next, p-toluenesulfonic acid(23.1 mg, 1.1 eq) was added and the sticky slurry was stirred at 50° C.over a period of 20 minutes. Then, ethanol (250 μl, 5V) was added toobtain a slurry. The slurry was stirred at 50° C. over a period of 50minutes. Next, the slurry was spontaneously cooled to room temperatureand the obtained solid was isolated using centrifuge. The isolated solidwas washed once with Water:Ethanol (1 ml, 2V, 4:1) and dried in a vacuumoven at 45° C. over a period of 18 hours to afford yellow solid. Theobtained solid was analyzed by X-ray powder diffraction and the XRPDpattern is presented in FIG. 15 .

The invention claimed is:
 1. A crystalline form of Belumosudil Mesylatedesignated form M1, which is characterized by data selected from one ormore of the following: (a) an XRPD pattern having peaks at 7.1, 17.2,20.3, 21.5 and 25.5 degrees 2-theta±0.2 degrees 2-theta; (b) an XRPDpattern substantially as depicted in FIG. 5 ; (c) an XRPD pattern havingpeaks at 7.1, 17.2, 20.3, 21.5 and 25.5 degrees 2-theta±0.2 degrees2-theta, and also having any one, two, three, four or five additionalpeaks selected from 8.4, 15.5, 16.8, 19.5 and 22.1 degrees two theta±0.2degrees two theta; (d) an X-ray powder diffraction pattern having peaksat 7.1, 8.4, 15.5, 16.8, 17.2, 19.5, 20.3, 21.5, 22.1 and 25.5 degrees2-theta±0.2 degrees 2-theta; (e) a solid state 13C NMR spectrum withcharacteristic peaks at 137.8, 133.8, 122.5, 118.3 and 111.6 ppm±0.2ppm; (f) a solid state ¹³C NMR spectrum having the following chemicalshift absolute differences from reference peak at 167.2 ppm±1 ppm: 29.4,33.4, 44.7, 48.9 and 55.6 ppm±0.1 ppm; or (g) a solid state ¹³C NMRspectrum substantially as depicted in FIG. 16, 17 or 18 .
 2. Thecrystalline form according to claim 1, wherein the crystalline form isan anhydrous form.
 3. The crystalline form according to claim 1, whichcontains no more than about 20% of any other crystalline forms ofBelumosudil Mesylate.
 4. The crystalline form according to claim 1,which contains no more than about 20% of amorphous Belumosudil Mesylate.5. A pharmaceutical composition comprising the crystalline formaccording to claim 1 and at least one pharmaceutically acceptableexcipient.
 6. A process for preparing a pharmaceutical compositioncomprising combining the crystalline form according to claim 1 with atleast one pharmaceutically acceptable excipient.
 7. A method of treatingGraft-Versus-Host Disease, Systemic Sclerosis, Fibrosis, PlaquePsoriasis, or Systemic Scleroderma, comprising administering atherapeutically effective amount of the crystalline form according toclaim 1 to a subject in need of the treatment.
 8. The method of claim 7,wherein the Graft-Versus-Host Disease is Chronic Graft-Versus-HostDisease.
 9. The method of claim 7, wherein the Systemic Sclerosis isDiffuse Cutaneous Systemic Sclerosis.
 10. The method of claim 7, whereinthe Fibrosis is Idiopathic Pulmonary Fibrosis.